1. Technical Field
The present invention is related to a method of controlling graft versus host reaction. More particularly, the present invention is related to the prevention or amelioration of graft versus host disease (GVHD) in bone marrow transplantation by succinylacetone (SA).
2. State of the Art
Successful bone marrow transplantation has wide application to a variety of serious diseases ranging from leukemia to radiation caused illness. Efficacy of bone marrow transplantation in the treatment of a number of human disorders is a subject of active investigation for such conditions as severe combined immunologic deficiency, aplastic anemia, genetic disorders of the marrow such as thalassemia major and malignant disorders, including acute leukemia (relapsed once), acute nonlymphocytic leukemia in first remission, chronic granulocytic leukemia and the like. Since donor and recipient are rarely genetically identical, some degree of histocompatability antigen mismatch is inevitable in most bone marrow transplants. Even where donors and recipients are HLA matched, that is, matched for the antigens of the major histocompatability complex (MHC) loci, problems can arise from mismatched minor loci.
The most serious problem which occurs in allogeneic bone marrow transplants is the development of graft versus host disease (GVHD). In the recipient whose capacity for immune rejection of the allogeneic transplant is genetically deficient or has been eliminated by means of radiation and/or cytotoxic drugs, the immunocompetent cells in the graft can recognize foreign antigens in the recipient and attack various tissues (gastrointestinal tract, skin, lymphoid organs and liver), leading to acute GVHD and a fatal outcome in some patients. Furthermore, GVHD can occur in a chronic form which can also be fatal. Management of this problem involves both prophylaxis and treatment of the actual disease. It has been reported that despite methotrexate prophylaxis for the first 100 days, 35-50% of treated patients still developed GVHD, and similar results have been reported with cyclophosphamide and cyclosporin A. These values are for the condition where the donor and recipient are HLA matched. The incidence of GVHD approaches 100% for HLA mismatched donor-recipient combinations. Therefore, GVHD severely limits the use of bone marrow transplantation to HLA matched donor recipient combinations. Thus, there is a great need for better agents for the prophylaxis and control of GVHD.
Succinylacetone (SA, 4,6-dioxoheptanoic acid) was discovered in the urine of patients with hereditary tyrosinemia (Linddblad, et al., 1977. Proc. Natl. Acad. Sci. USA, 74:4641-4645). It is an inhibitor of .delta.-aminolevlinic acid dehydrase (Tschudy, et al., 1981. J. Biol. Chem. 256:9915-9923; and Sassa, et al., 1983. J. Clin. Invest. 71:625-634), the second enzyme of the heme biosynthetic pathway and has immunosuppressive activity (Tschudy et al., 1982. J. Lab. Clin. Med. 99:526-532).